After traumatic brain injury (TBI), systemic hypotension causes secondary ischemic brain injury that markedly worsens mortality and neurologic outcome. We will test the hypothesis that, as a consequence of TBI and posttraumatic hemorrhagic hypotension, neurotoxic concentrations of Zn2+ are released from presynaptic glutamatergic vesicles in association with glutamate, enter postsynaptic neurons through receptor-associated calcium channels (especially AMPA/kainite receptors) and voltage-operated calcium channels, and worsen outcome by accumulating in postsynaptic neurons. Specific aim 1: In rats subjected to TBI with our without hypotension, we will test the hypothesis that neuronal Zn2+ accumulation is related to Zn2+ release, which is proportional to the severity of TBI and hypotension and the interval between TBI and hypotension. Methodologies: microdialysis (Zn2+ and glutamate); staining with the Zn2+-specific dye TSQ (intracellular Zn2+ accumulation); vanadium acid fuchsin (VAF) staining (acute cell injury); staining for DNA fragmentation (TUNEL); ribonuclease protection assays (apoptosis); neuronal counts (histopathologic outcome), and beam walking, beam balance and the Morris water maze (neurobehavioral outcome). Specific aim 2: In rats subjected to moderate TBI with or without hypotension, we will address the hypothesis that after TBI, Zn2+ enters neurons through receptor-associated calcium channels and voltage-operated calcium channels (VOCCs) and that entry through (VOCCs) is enhanced by posttraumatic brain tissue acidosis. Interventions: the NMDA receptor antagonist MK-801, the AMPA/kainite receptor antagonist LY300164, the L-type calcium channel antagonist nimodipine, and increases and decreases in extracellular pH. Methodologies: microdialysis, TSQ staining, and VAF staining. Specific aim 3: In rats subjected to moderate TBI and hypotension, we will address the hypothesis that after, TBI and hypotension, modifying extracellular Zn2+ concentrations will modify neurobehavioral and histopathologic injury. We will test this hypothesis by using intracerebroventricular (icv) injection of Zn2+ and by icv injection of the specific Zn2+-binding apoenzyme of carbonic anhydrase. Methodologies: identical to specific aim 1 plus monitoring for signs of neurologic zinc deficiency.